The overall objective is the same as that of the previous funding period - to develop a group of Tc-99m labeled brain perfusion imaging agents for evaluating patients with abnormal cerebrovascular circulation. The Tc-99m agents will cross the blood-brain barrier (BBB), have high first pass brain extraction, show prolonged regional brain retention, and display distribution pattern quantitatively correlated to regional cerebral blood flow (rCBF). In addition, the agents will have several useful characteristics - readily prepared in a kit form, inexpensive and giving low radiation dose to patients, all of which will make these materials suitable for widespread clinical application. Current Tc-99m brain imaging agents are compounds that cannot pass through the blood-brain barrier (BBB). In areas of brain where the BBB is no longer intact, the imaging agents show a positive uptake. This type of brain imaging study is now seldom done, the emphasis in nuclear medicine brain imaging has shifted from detecting structural defects of the BBB to studying the brain perfusion, metabolism and receptor binding. Brain perfusion imaging with single-photon emission computed tomography (SPECT), which is capable of detection of small abnormality in regional brain perfusion, requires the proposed Tc-99m agents. In the past funding period, we have chosen to study Tc-99m BAT (bisaminoethanethiol) compounds. We have demonstrated that the Tc-99m complexes penetrate the BBB in rats and monkeys. In addition, several new BAT compounds with lipophilic and amine side chain (trapping functional group) were also studied. These lipid-soluble Tc-99m complexes can cross the BBB and display significant retention and fixation of regional distribution, which are essential properties for a Tc-99m brain perfusion agent. In the next three years we propose to prepare a series of new BAT ligands and evaluate the Tc-99m labeled complexes in rats and monkeys. For those agents which show potential for clinical application, we will use quantitative autoradiography to correlate the regional brain distribution with the regional cerebral perfusion in rats. It is highly probable that, based on this BAT ligand, we will be able to develop a useful brain imaging agent with all of the required properties.